Antiparasitic compositions and use thereof



United States Patent Ofiice 3,253,986 Patented May 31, 1966 Where R and R each independently represent a hydrogen atom or a methyl group and X is a physiologically acceptable anion. As examples of some of the many physiologically acceptable anions contemplated, there may be mentioned the chloride, bromide, iodide, nitrate, bisulfite, bisulfate, hemisulfate, perchlorate, acetate, palmitate, stearate, hemipamoate, picrate, decanesulfonate, 4-chloro-2 (5 chlorosalicyl)phenoxide, hydroxy naphthoate, dodecylsulfate, cyclohexanesulfamate, phenolphthalein, trichlorophenoxide, 2,2'-thiobis-(4,6-dichlorophenoxide), deoxycholate, 7-chloro-4-hydroxy 3 quinolinecarboxylate, dihydroxyisonicotinate, bromonaphthoxide, hemiadiapate, p-toluenesulfonate, hemi-(5,5'-thiodi'- salicylate), 3,5-dichlorosalicylate, taurocholate, dioctylsulfosuccinate and 2,6-di-iodo-4-nitrophenoxide. In general, the choice of anion is not critical since the abovementioned cation constitutes the antiparasitically active moiety. :Moreover, the selection and provision of salts in general will be understood by those skilled in the art in accordance with methods and considerations which will be known to them. Preferred compositions of the invention are those which include as an active ingredient imidazo[1,2-a:3,4-a']diquinolinium nitrate and/ or trichlorophenoXide.

Parasitic infection caused by pinworms, hookworms, round worms and other helminths is a serious medical problem in many areas of the world. Various agents have been proposed for the treatment of parasitic infection. At the present time, however, these agents fail to meet one or more of the several criteria generally considered to be desirable in an antiparasitic agent. Such an agent should, for example, be highly active orally and should be relatively free of toxic or other undesired side effects. It should be well tolerated and provide a substantial margin of safety between the effective and toxic dosages. It

should also provide the desired effect in a single dose and should preferably have broad spectrum 'antiparasitic activity.

It is therefore an object of the present invention to provide anthelmintic compositions which are highly active and well tolerated.

It is also an object to provide anthelmintic compositions which are active when administered by the oral route and which provide a significant margin of safety between effective and toxic dosages.

It is a further object to provide compositions having not only broad spectrum anthehnintic activity but also other pharmacological properties such as antibacterial, antiamebic and antitrichomonal activity.

These and other objects, features and purposes of the invention, which will be apparent from the following description of the invention, are realized by the use of compositions containing a therapeutically effective amount of the aforementioned salt of imidazo[1,2-a:3,4-a']diquinolin-lS-ium cation. 'The compositions of the invention are characterized by their high degree of effectiveness against a wide variety of helminths including pinworms, hookworms, whipworms and round worms. The compositions are orally active in a single dose and are relatively free of undesirable side-effects at therapeutic levels. In addition,- the compositions also desirably provide antibacterial, antiamebic and antitrichomonal effects thereby affording the possibility for single treatment of plural infection caused by more than one type of pathogen.

The imidazo[l,2 a:3,4 a']diquinolin 15 ium compounds having the above formula can be produced con-.

veniently in iodide salt form by condensing a quinoline compound of formula with a quinaldine compound of formula \N/ CH3 in the presence of an inert organic solvent containing iodine; where R and R have the above-specified signifidance. The resulting iodide salt compounds can be converted to any other desired anion salt in accordance with known procedures such as ion exchange. In particular, to produce a salt other than the iodide, an aqueous solution of the iodide salt is contacted in a suitable solvent such as water or aqueous alcohol, with a strong base ion exchange resin in the hydroxyl form. The resulting hydroxide solution is acidified with an equivalent of acetic acid to provide the acetate salt, and the latter is reacted with the sodium or potassium salt of an acid having the desired anion, thereby providing the corresponding anion salt by metathesis; alternatively, and especially in the case of an acid which is water-soluble, the hydroxide solution can be allowed to react directly with the acid to form the desired salt.

According to the present invention, antiparasit-ic compositions are produced by formulating salts of imidazo- [1,2-a:3,4-a']diquinolin- 15 -ium cation in dosage unit 3 form. Such compositions are constituted with pharma: ceutical carriers or diluents. In view of the oral activity of such salts, dosage unit forms for oral administration are particularly suitable. For this purpose, one or more of the salts can be incorporated with pharmaceuticallyacceptable solid or liquid diluents. Solid carriers and diluents are particularly suitable and include sugars such as lactose and sucrose; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose and cellulose acetate phthalate; gelatin (including hard and soft shell capsule); talc, corn starch, stearic acid and magnesium stearate. Liquid carriers and diluents suitable for use include vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyethyelne 'glycol; propylene glycol; glycerine; sorbitol; ethanol; and water. Suitable preservatives and flavoring agents can also be incorporated in such compositions. In the production of dosage forms such as tablets, an enteric coating or sugar coating can be applied to make the medicament more palatable. If administration by the parenteral route is desired, the composition can be formulated in ampoule form as a suspension or solution in a liquid diluent. Other therapeutic agents can also be incorporated with the compositions.

The aforementioned compositions can be employed in suitable dosage for the treatment of animals such as house pets, cattle, sheep, swine and poultry. For the treatment of animals, it is convenient to incorporate the imidazodiquinolinium salt in a physiologically compatible excipient such as a dietary component of the animal to be treated. Thus, the animal can receive its medication with its normal food intake. For example, one such medicated feed suitable for use in the treatment of animals of the herbivorous type is provided by blending one part by weight of imidazodiquinolinium salt with four parts of soybean oil meal and mixing the resulting blend in suitable dosage with the normal grain ration which may be a total ration or one to be supplemented by hay or roughage.

The percentage of imidazo[1,2-a:3,4-a']diquino1in-15- ium salt in the compositions can be varied within wide limits but, for practical purposes, is preferably present in a concentration of at least by weight. As will be appreciated, the upper-concentration limit is not critical.

According to the invention, the compositions are administered in a single oral dose. The dosage for veterinary purposes is such as to provide about 121.5 to about 100 mg. of imidazodiquinoliniurn salt (as cation equivalent) per kg. of body weight.

In the preparation of dosage unit forms such as tablets or capsules, the quantity of medicament furnished by each dosage unit form is selected such that the proper dose can be reached by administering either one or. a reasonable number of the dosage units. For convenience of manufacture and ease of administration, it is preferable that such dosage forms contain at least 12.5 mg. and up to one gram of imidazodiquinolinium salt per unit.

The invention is illustrated by the following examples showing various suitable dosage forms and the preparation thereof.

Distilled water q.s. ad cc 100 (1) Wet the diquinolinium iodide with the polyvinylpyrrolidone dissolved in cc. of water. of water and add to (1).

(2) Hydrate the water-swellable silicate in 10 cc.

(3) Add to (2) the sodium carboxymethylcellulose, sodium citrate, citric acid, sodium benzoate and the sugar. Mix until dissolved.

(4) Dissolve the raspberry flavor inthe alcohol and add to (3).

(5) Dissolve the red dye in 2 cc. of water and add to (4).

(6) Check pH and adjust to pH 5.0 (7) Bring volume up to 100 cc. with distilled water.

The diquinolinium iodide for the above suspension formula was prepared as follows:

To a stirred solution of 516 g. (4.0 moles) of quinoline and 143 g. (1.0 mole) of quinaldine in 350 ml. of chlorobenzene at room temperature was added 508 g. (2.0 moles) of iodine in one portion. The temperature of the reaction mixture rose rapidly to 47 and finally reached 61 over the next 20 minutes. The deep red mixture was then heated at 110 for 24 hours, cooled to and filtered. The filter cake was washed several times with acetone and dried to give 311 g. of crude product. The crude product was suspended in 450 ml. of ethanol and 450 ml. of pyridine and the well-stirred mixture was heated on a steam bath for 30 minutes. The suspension was cooled, the product was removed by filtration, washed with acetone and dried; M.P. 325 C. Water solubility, 0.01 g./100 ml.

In place of imidazo[1,2-a:3,4-a]diquinolin-lS-ium iodide in the above suspension formula, one can use corresponding 3-methylor 3,10-dimethy1, derivative prepared as follows:

(a) .3 methylimidazo[1,2-a:3,4-a]diquinolin-IS-ium iodide.6-methylquinoline (133 g.), quinaldine (33.6 g.) and iodine (119 g.) in chlorobenzene (80 ml.) were heated at 100 C. for 16 hours. The mixture was cooled to C. and the crude product removed by filtration. It was Washed with acetone and then crystallized from N,N-dimethylformamide; M.P. 296297 C., slightly soluble in water.

(b) 3,10 dimethylimidaz0[1,2 a:3,4 a']diquinolin- 15 ium iodide.6 methylquino-line (126 g.), 2,6 dimethylquinoline (34 g.) and iodine (114 g.) in chlorobenzene ml.) were heated for 24 hours at C. N,N-dimethylformamide (100 ml.) was then added to the hard residue and the mixture heated on a steam bath until the solid was tractable. The product was removed by filtration, washed with acetone and crystallized from 700 ml. of N,N-dimethylformamide; M.P. 337 C.

EXAMPLE, 2 Formula for solution Imidaz0l[1,2 a:3,4 a'Jdiquinolin-lS-ium propio- (1) Dissolve the diquinolinium salt in-the alcohol. Add the polyethylene glycol, sorbitan monostearate, oil of orange and glycerine.

(2) Dissolve the sugar in 30 cc. of water, add the sodium saccharin.

(3)Mix 1 and 2 with rapid stirring.

(4) Filter.

The diquinolinum propionate salt for the above solution formula was prepared from the corresponding iodide salt, as follows:

To a stirred suspension of 5 g. of strong basic ion exchange resin in the hydroxyl form (Amberlite IRA-410) in 2 liters of water was added 250 g. (0.63 mole) of imidazo[1,2-a:3,4-a]diquinolin-l-ium iodide at room temperature and after two hours the resin was removed and washed with water. The combined filtrate and washing contained 0.60 mole of the corresponding diquinolinium hydroxide by titration. To this solution was added 44.4 g. (0.60 mole) of propionic acid. The resulting solution was concentrated to near dryness in vacuo. The residue was crystallized from aqueous acetone to give 211 g. (85%) of the propionate salt, tetrahydrate; M.P. 141 C.; water solubility, 35.1 g./O ml.

In like manner, any of the following imidazo- [1,2-a:3,4-a']diquinolin-l5-ium salts can be used in place of the propionate salt in the above solution formula, these salts being conveniently prepared, as above, from the diquinolinium hydroxide by treating an aqueous solution of the latter with the appropriate acid:

I.P., Water Salt C. solubility, g./100m1.

Chloride, -4 H2O 2.0 Bromide, 3 1120.- 0. 32 Bisulfate, -H 0 290 4.18 Perchlorate 280 l-hexanesulfonate, -2HzO 171 2. 0 4-chlorobenzenesulfonate 261 0. 07 itrat 273-275 0. 47

EXAMPLE 3 Formula for soft gelatin capsules (250 mg.)

G. Imidazo[ 1,2 a: 3,4 a]diquinolin -ium 2,4,5-trichlorophenoxide, dihydrate 250 Sorbitan mono-oleate (Tween 80) 50 Lecithin-Soy Corn oil 600 (l) Dissolve the lecithin-soy in the corn oil. Add

the sorbitan mono-oleate and stir until fully dispersed.

(2) Slowly add the trichlorophenoxide salt to the oil vehicle. Stir until completely suspended. Pass through a paint mill and fill into 16-minim oblong soft-gelatin capsules. Yield, approximately 1000 capsules.

The trichlorophenoxide salt for the above formula was prepared from the iodide salt as follows:

To a stirred suspension of 500 g. of strong base ion exchange resin in the hydroxyl form (Amberlite IM- 410, registered trademark) in 2 1. of water was added 250 g. (0.63 mole) of imidazo[1,2-a:3,4-a]diquinolin- 15-ium iodide at room temperature and after 2 hours the resin was removed by filtration and washed with water. The filtrate, plus the washing, contained 0.60 mole of imidazo[1,2-a:3,4-a']diquino1in-15-ium hydroxide by titration. To this solution was added 36 g. (0.60 mole) of acetic acid. To the resulting solution containing imidazo [1,2-a:3,4-a]diquinolin-15-ium acetate was added an aqueous solution of 0.60 mole of the sodium salt of 2,4,5- trichlorophenol (prepared fro-m 24 g. of sodium hydroxide,

118 g. of 2,4,5-trichlorophenol and 200 ml. of water).

The resulting precipitate was removed by filtration, washed with water and dried. Yield of the 2,4,5-trichlorophenoxide salt was 285 g. (90%); M.P. 217. Sol. (H O): 0.012 g./100 ml.

In like manner, any of the following imidazo[1,2-a:3,4- a]diquinolin-15-ium salts can be used in place of the trichlorophenoxide salt in the above capsule formula, these salts being conveniently prepared, as above, from the acetate salt by treating an aqueous solution of the M.P., Water Salt C. solubility, g./ ml.

Palmitate, -3H 0 1 14 147 0.019 Pierate 264 Decanoate, -4H20 121-122 0.137 Hemi-pamoate 2% H O 275-280 (a) Bisulfite, 2H2 270 0.4 l-decanesulfonate, 'HQO 91 0.033 4chlor0-2-(fi-ehlorosalicyl)-phen0x1de 3 252 0.0016 3-hydroxy-2-naphthoate. 237 0. 016 Dodeeyl Sulfate, -2H O 98-100 0. 0088 Phenolphthaleiu, -H O 205 Deoxycholate, -4Hz0 254 0.013 7-ehl0r0-4-hydroxy-B-quinolinecarboxylate,

-3Hz0 223 0. 0011 2,6-dihydroxyisonicotinate, -2H O 235 1-bromo-2-naphthoxide, -2H O 148-150 0.04 Hemi-adipate, 3% H O 171 Hemi-5,5-thiodisalioylate, 2% 113-115 0.00033 l-octadecanesulfonate, 'BH O 135 0.0071 Taurocholate, -3H2O 3 0. 093 3,5,S-trimethylhexane-sulfonate, -H O 175 0. 26 Dioctylsulfosuceinate, 211 0.- Laurate 2%Hz0 128 2,6-diio o4-nitrophenoxide. 232 Oetanoate, -3H O 126 3,5-dichlorosalicylate 174-176 2,2-thiobis(4,6-dichlorophenoxide) 261-263 0. 0038 1 S1. Sol.

2 Insol.

3 (Dee) EXAMPLE 4 Formula for coated tablets (500 mg.)

10-methylimidazo[1,2-a:3,4-a']diquinolin-15-ium bromide, dihydrate g 500 Corn starch, sifted g (1) Blend the bromide salt and 75 g. of corn starch.

(2) Soak the gelatin in 100 ml. of cold distilled water for 30 minutes and then heat to dissolve.

(3) Suspend 15 g. of starch in 30 ml. of distilled Water and add to the gelatin solution. Heat and stir until a paste is formed.

(4) Wet granulate the powder mixture of (1) with the paste of (3). Finish granulating with distilled water if necessary.

(5) Screen the wet granulation through a No. 6 stainless steel screen.

(6) Dry overnight at -130 F.

(7) Reduce the dried granulation through a No. 14 stainless steel screen.

(8) Blend in the magnesium stearate and 20 g. of starch.

(9) Compress the blend on a rotary tableting machine using 7 deep concave punches. Yield, approximately 1000 tablets each containing 500 mg. of the diquinolinium bromide salt.

The diquinolinium bromide for the above tablet formula was prepared from the corresponding iodide salt by ion exchange, as follows:

To a stirred suspension of 500 g. of strong basic ion exchange resin in the hydroxyl form (Amberlite IRA- 410) in 2 liters of water was added 246 g. (0.60 mole) of 10-methylimidazo[ 1,2-a 3 ,4-a]diquinolin-15-ium iodide at room temperature; After 2 hours, the resin was removed, washed with water, and the resulting solution of quaternary hydroxide treated with excess hydrobromic acid. The product which separated 10-methylimidazo [1,2-a:3,4-a'1diquinolin-l5-ium bromide, dihydrate) was washed with ice water and dried under vacuum; M.P., 307 C. Water solubility, 0.26 g./ 100 ml.

The iodide salt starting material is prepared by heating at 100 C. for 12 hours a mixture of iodine (508 parts by weight), 2,6-dimethylquinoline (320 parts by weight) and quinoline (120 parts by volume), extracting the reaction mixture successively with ether, acetone, and water, and crystallizing the residue from ethanol-water; M.P. 319 C.

What is claimed is:

1. A veterinary antiparasitic composition in dosage form comprising an eifective antiparasitic amount of imidazo[1,2-a:3,4-a']diquinolin-15-ium salt having the wherein R and R are members selectedfrom the group consisting of a hydrogen atom and a methyl group and X* is a physiologically acceptable anion, and a carrier for the salt.

2. A composition according to claim 1 utilizable as a dietary component wherein the salt is present in an amount sufiicient to provide about 12.5 to about 100 mg. of imidazodiquinolinium cation per kg. of body weight when ingested in the daily feed ration.

3. A method of treating parasitic infection in animals which comprises administering to the animal host a composition in dosage unit form containing as active ingre- 8 dient an eflective antiparasitic amount of imidazo [1,2-a:3,4-a']diquinolin-lS-ium salt having the formula wherein R and R are members selected from the group consisting of a hydrogen atom and a methyl group and X- is a physiologically acceptable anion and a carrier for the active ingredient.

4. A method according to claim 3 wherein a composition containing imidazo[1,2-a:3,4-a]diquinolin-15-iurn nitrate is employed.

5. A method according to claim 3 wherein a composition containing imidazo[1,2-a:3,4-a'1diquinolin-15-iurn trichlorophenoxide is employed.

6. A method according to claim 3 wherein the com position is administered to an animal host in a dosage sufficient to provide imidazodiquinolinium salt within the range of about 12.5 to' about mg. per kg. of body weight.

No references cited.

JULIAN S. LEVITT, Primary Examiner. FRANK CACCIAPAGLIA, IR.', Examiner.

N. G. MANN, Assistant Examiner. 

3. A METHOD OF TREATING PARASITIC INFECTION IN ANIMALS WHICH COMPRISES ADMINISTERING TO THE ANIMAL HOST A COMPOSITION IN DOSAGE UNIT FORM CONTAINING AS ACTIVE INGREDIENT AN EFFECTIVE ANTIPARASITIC AMOUNT OF IMIDAZO (1,2-A:3,4-A'')DIQUINOLIN-15-IUM SALT HAVING THE FORMULA 